Novel Antimicrobial Host Defense Peptides: Design and Immunomodulatory Function

点击翻译按钮获取中文摘要

Antimicrobial resistance (AMR) is an increasingly important global health concern, with simple bacterial infections becoming once again prevalent and lethal. The recent SARS-CoV2 pandemic has further exacerbated resistance, because antibiotics are being heavily overprescribed to COVID-19 patients even when only small proportions display bacterial co-infection. Host defense peptides (HDPs) are a viable solution against resistant bacteria due to their diverse mechanisms of action, such as direct bacterial killing as well as immunomodulatory properties. Despite their promise, HDPs are however seldom used in a clinical setting because their therapeutic efficacy is limited by rapid degradation, systemic toxicity, and low bioavailability. In the last 6 years, the Straus group has done extensive work to improve the applicability of HDPs. New peptides, which are highly active against resistant bacteria, were generated and their mechanism of action was elucidated. Moreover, formulation and conjugation strategies that mitigate the limitations of HDPs were developed. The resulting approaches show tremendous promise. However, in order to further broaden the usage of HDPs, three important areas require further in-depth study: 1) understanding how immunomodulatory HDPs (iHDPs) function at a molecular level; 2) tailoring delivery strategies for iHDPs by understanding how conjugation impacts the mechanism of action; and 3) developing approaches to repurpose commonly used antibiotics in order to have ready solutions to the AMR problem. Specifically, this proposal outlines objectives that will enable a team of diverse HQP to develop as independent researchers, with strong training in interdisciplinary, collaborative research and thorough knowledge of biophysical techniques (e.g. NMR, ITC, CD, etc.). Trainees will benefit from a work environment where equity, diversity and inclusion are core values: most trainees in the Straus group are women and from visible minorities. To understand the mechanism of action of iHDPs (aim 1), two PhD students will determine how these peptides affect macrophage differentiation by studying HDP/macrophage interactions, a new area of research. They will also investigate how amino acid composition modulates immunomodulatory activity. In terms of conjugation (2), two PhD students will further fine-tune current approaches and adapt them to iHDPs, as well as determine (e.g. using whole bacterial cell NMR) how the mode of action of the polymer-HDP conjugate differs from the HDP alone. Finally, using our knowledge on conjugation, a PhD student will devise methods to create new antibiotics (3) consisting of commonly used molecules plus HDPs. In this way, the benefit of current antibiotics (high activity, low toxicity) can be harnessed, while minimizing resistance effects. Overall, the proposed program will ensure that novel fundamental knowledge required to address the AMR problem is obtained, so that tangible solutions can be developed.